The placenta significantly limits fetal glucocorticoid exposure and undergoes cell-specific transcriptomic remodeling in response to maternal stress in mice

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Prenatal stress is a well-established risk factor for offspring neurodevelopmental, cardiovascular, and metabolic disease, yet prevailing models largely have assumed fetal programming occurs primarily through direct maternal glucocorticoid transfer. However, key regulatory steps governing placental glucocorticoid handling remain poorly defined. Using a transgenic mouse model with placental O-linked N-acetylglucosamine transferase (Ogt) deletion that recapitulates prenatal stress phenotypes, we examined the placenta limitation of maternal corticosterone transfer and how placental OGT regulates maternal–fetal corticosterone kinetics. Ex vivo placental perfusion and in vivo corticosterone injection revealed that less than 5% of corticosterone reached the fetus and only 14–22% was metabolized, indicating strong placental restriction. Single-nucleus and bulk RNA-sequencing further demonstrated stress-associated transcriptional remodeling and identified the ABC transporter ABCA2 as a potential regulator of corticosterone placental efflux. Together, these findings support the conclusion that while maternal glucocorticoids can directly alter the placenta, their impact on the fetus is likely indirect, supporting a placental barrier mechanism limiting fetal exposure and that placental responses may play a more prominent role in stress-associated developmental programming than previously appreciated.

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